Pain can exerted in different forms and normally serves as a warning signal to protect the body from harmful stimuli or promote healing after injury. However, under pathological conditions, pain is sensed without harmful stimuli and can persist. Chronic pain is a long lasting pain that persists longer than the temporal course of natural healing of the underlying causative injury or disease. It serves no beneficial or protective function. Chronic pain is a major debilitating disorder that affects one-third of the general population during their adult life-span.
Cancer pain is one of the most common types of chronic pain and demonstrates nociceptive components due to tumor growth and neuropathic components due to tumor induced nerve damage. It can further involve structural damage, nerve entrapment and damage, inflammatory processes that lead to the disruption of normal tissue metabolism, the production of inflammatory prostaglandins and cytokines, and tissue damage.
The cyclic AMP signaling pathway is the first pathway identified in regulating pain sensitivity. Recent study suggests that the cAMP receptor (the classic cAMP-dependent protein kinase (PKA)) is more closely related in regulation of acute pain while cAMP sensors (exchange proteins directly activated by cAMP (EPAC1 and EPAC2)) contribute to development of chronic pain. To date, the main analgesics employed for treatment of chronic pain are opiates and non-steroidal anti-inflammatory drugs (NSAIDS). Both classes of drugs can produce severe side-effects—NSAIDS can cause gastric ulceration and renal damage and opiates can cause nausea, constipation, confusion and dependency problems. Opioids fail to produce pain relief in all individuals suffering chronic pain, even at high doses, and development of analgesic resistance to opioids complicates their utility for long-term therapy. In particular, cancer pain treatment requires the use of unacceptably high levels of opiates bringing with it side-effects and at least 20% of treated patients still have uncontrolled pain.
Accordingly, there is a critical medical need to identify new pharmaceutically active compounds that interfere with key steps of the chronic pain process and particularly for the treatment and/or prevention of chronic nociceptive pain and/or symptoms of chronic nociceptive pain.